We propose to study patients who are candidates for active surveillance (AS) to identify imaging and gene expression signatures that distinguish indolent from aggressive prostate cancer and to better understand the mechanisms underlying progression. We will apply novel MRI techniques (i) for quantitative multiparametric MRI (MP-MRI) findings to define habitats within the prostate; (ii) to guide prostate biopsies to MP-MRI defined lesions and determine histopathologic associations with habitats; (iii) to develop signatures based on high throughput analysis of imaging features (radiomics); (iv) to relate biopsy oligonucleotide gene expression signatures to inform on the molecular characteristics associated with imaging signatures (radiogenomics); and (v) develop models of progression (conversion to treatment) that incorporate clinical, histopathologic, imaging signatures and gene expression signatures. A Phase II AS trial of prostate cancer patients is designed to acquire MP-MRI, prostate tissue and biofluids at yearly intervals to relate to MP-MRI results and the primary endpoint of progression. The techniques that we propose have the potential to better identify indolent versus aggressive disease, thereby reducing the effects of overdiagnosis. The Specific Aims are: Aim 1. To assess the overall rate and temporal distribution of progression in men undergoing MP-MRI assessments and directed prostate biopsies for AS in a prospective Phase II trial. Aim 2. To establish MP-MRI habitats and use radiomics analysis of MP-MRI features to develop signatures related to adverse histopathologic parameters and patient progression. Aim 3. To molecularly characterize the MP-MRI-directed prostate biopsies obtained, develop a gene expression signature of indolent versus aggressive prostate cancers, and relate this information to the radiomics-derived signatures. We propose that quantitative MP-MRI parameters will be representative of histopathologic and molecular parameters and be an important adjunct to defining risk of progression and, consequently, reduce the rate of unnecessary biopsies.